ABSTRACT AD and related diseases (ADRD) represent a significant cognitive threat to our aging population. There is no cure for ADRD, which is partly due to poor understanding of how aging and inflammation impacts tau pathogenesis. It is expected that healthcare costs in the United States associated with AD patient care will exceed $1 trillion by 2050. As a result, there is an urgent need to identify clear molecular mechanisms that ameliorate risk for AD. Epidemiological evidence suggests a potential link between alcohol abuse and AD; however, the cellular and molecular mechanisms underlying the potential associated risk of alcohol abuse and AD development is a largely unexplored research area. Microglia are the resident immune cells of the brain and have been associated with neuroinflammatory processes that occur from chronic alcohol exposure. Our collaborative team has been actively investigating the activation phenotypes of ethanol-treated microglia, which has led to the discovery of novel biological pathways that could be affected and consequently influence the unique activation phenotype observed for microglia after acute ethanol exposure. We have strong data that suggest histone methylation and the histone demethylase KDM5B play a role in modulation of microglial activation phenotype during ethanol exposure, which is the focus of our currently funded R01 project: ?The role of histone demethylase KDM5B in ethanol-induced microglial activation?. We will extend our studies in this administrative supplement to investigate microglial phenotype in aged mice that exhibit tau pathology (induced by intracranial AAV-hTau injection) and determine the effect of chronic ethanol exposure in early adulthood on tau pathology development later in life. Based on literature precedent and data generated from our lab, we hypothesize that previous ethanol exposure induces changes in microglial activation phenotype, which is regulated by histone methylation, and that these changes in microglial epigenetic state/function can persist into late adulthood and exacerbate tau pathology. To test our hypothesis, we will determine the impact of previous chronic ethanol exposure on the microglial histone methylation code and related activation phenotype associated with tau pathology development in mice. This project will be the first study of its kind to accurately classify the activation phenotype of microglia in order to better understand potential long-lasting microglial functional changes that occur after chronic ethanol exposure and if these changes can influence neuroinflammation and tau pathology in later adulthood. The proposed administrative supplement is highly responsive to NOT-AG-18-039: Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease. The results from the study could provide a strong foundation for future mechanistic studies aimed to identify molecular factors associated with alcohol and its potential link to AD pathogenesis.